PROJECT SUMMARY/ABSTRACT Injection drug users (IDUs) constitute 60% of the approximately 5 million people in the U.S. infected with hepatitis C virus (HCV). Up to 90% of HIV-infected IDUs are also infected with HCV. HCV treatment leading to sustained viral response (SVR) is associated with increased survival, but to date IDUs have had poor access to HCV care and their success in HCV treatment has been limited. Although past HCV therapies have been relatively ineffective in genotype-1 infected patients, newer regimens are substantially improved. With direct- acting antiviral agents, HCV treatment delivered within large clinical trials leads to SVR or cure in over 70% of genotype-1 infected patients (including HIV/HCV-coinfected patients), compared to 45% with previous therapies. However, SVR rates are as low as 14% in real-world settings. The majority of patients who fail to achieve SVR will develop drug resistance, but the optimal adherence level to minimize resistance is unknown. If HCV treatment continues to be delivered within current models of care, most IDUs will not only fail treatment and develop resistance, but may transmit resistant viruses to others. Because the life- and costsaving benefits of new HCV treatments will not be realized unless we determine optimal models of care for the majority of HCV-infected patients, we are proposing a randomized controlled trial of three models of care. We have previously developed a multidisciplinary model of HCV care which integrates on-site primary care (including HIV care), substance abuse treatment, psychiatric care, and HCV-related care within opiate agonist treatment clinics. To maximize treatment outcomes, we piloted two models of intensive HCV-related care: directly observed therapy (DOT), and concurrent group therapy (CGT). In our DOT model, pegylated interferon is administered once weekly, and one daily dose of oral medication is administered at the methadone window. In our CGT model, patients initiate HCV treatment within a once weekly treatment group which provides powerful social support to mitigate fears of side effects, promote efficient education, and deliver weekly injections. It is unknown whether either model is better or more cost-effective than standard on-site care. In the proposed study, 150 IDUs (100 HCV-monoinfected and 50 HIV/HCV coinfected) with chronic HCV (genotype 1) will be recruited from methadone clinics and randomized to one of three models of care: DOT; concurrent group treatment; or standard on-site care. Our specific aims are: 1) To determine whether either of two intensive on- site HCV treatment models (DOT or concurrent group treatment) is more efficacious than standard on-site treatment for enhancing adherence and SVR, and decreasing drug resistance; (2) To determine the incidence and factors associated with the development of drug resistance in IDUs; (3) To perform cost and cost- effectiveness analyses of each model; and (4) To examine the impact of HIV coinfection on adherence and virologic outcomes among HCV-infected IDUs.